Modulation of glucocorticoid receptor induction properties by core circadian clock proteins
Modulation of glucocorticoid receptor induction properties by core circadian clock proteins
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DOI：
10.1016/j.mce.2013.12.013
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发表时间：
2014-03-05
影响因子：
4.1
通讯作者：
Cho, Sehyung
中科院分区：
文献类型：
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作者：
Han, Dong-Hee;Lee, Yeon-Ju;Cho, Sehyung
糖皮质激素（GC）在机体代谢和免疫功能等多种生理过程中发挥重要作用。虽然GC合成和分泌的昼夜节律控制相对较好地理解，但靶组织内GC作用的昼夜节律控制仍然知之甚少。在这里，我们证明，时钟/BMAL 1，核心生物钟组件，降低最大GR反式激活（Amax）以及疗效（EC 50）的一种新的机制，需要结合到DNA和靶基因的反式激活。因此，我们观察到PER 1和PER 11，CLOCK/BMAL 1作用的主要靶点，降低最大GR反式激活，同时不影响功效。此外，我们观察到超激活的GRE依赖的转录BMAL 1或PERs缺陷的MEFs。此外，内源性GC靶基因表达与CLOCK/BMAL 1活性呈负相关。考虑到GC敏感性广泛涉及人类健康和疾病，这些结果为GC相关的生理学和病理学提供了有价值的见解。(C)2013爱思唯尔爱尔兰有限公司保留所有权利。
Glucocorticoid (GC) plays important roles in diverse physiological processes including metabolism and immune functions. While circadian control of GC synthesis and secretion is relatively well appreciated, circadian control of GC action within target tissues remains poorly understood. Here, we demonstrate that CLOCK/BMAL1, the core circadian clock components, reduces maximal GR transactivation (Amax) as well as efficacy (EC50) by a novel mechanism that requires binding to DNA and transactivation of target genes. Accordingly, we observe that PER1 and CRY1, the primary targets of CLOCK/BMAL1 action, reduce maximal GR transactivation while not affecting the efficacy. Moreover, we observe hyper-activations of GRE-dependent transcription in BMAL1- or PERs-deficient MEFs. In addition, endogenous GC target genes expression negatively correlates with the CLOCK/BMAL1 activity. Considering that GC sensitivity is widely implicated in human health and diseases, these results provide valuable insights into plethora of GC-related physiology and pathology. (C) 2013 Elsevier Ireland Ltd. All rights reserved.